CBD

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Introduction

CBD is the second most common Cannabinoid from the plant of cannabis. In contrast to THC, CBD is not psychoactive and the reduced side effects associated to its administration makes it as important as THC regarding its therapeutic properties. CBD is already used to treat epilepsy and to reduce symptoms of multiple sclerosis. Also, CBD can counteract the psychoactive effects of THC, making THC more easy to tolerate when high doses are required. CBD also has a huge therapeutic potential in a wide range of diseases due to its neuroprotective and immunomodulatory properties.

CBD has a low affinity for CB1 and CB2 of around 5 μM. However, CBD can functionally antagonize (prevent agonists from binding) at far lower concentrations (79 nM for CB1 and 138 nM for CB2)(Pertwee, 2008), which can be transiently achieved for instance by smoking/inhalation.

Mesenchymal stem cells may form a promising new method to regenerate nerve cells in degenerative diseases like Alzheimer’s. Treatment of mesenchymal stem cells with CBD prevented hallmarks of Alzheimer’s like β Amyloid plaques and neurofibrillary tangles (Libro et al., 2016) suggesting therapeutic potential. This effect was mediated by TRPV1 and the PI3K/Akt/GSK3β pathway. In rats, 10mg/kg CBD prevented reactive astrogliosis and neuronal degeneration after β Amyloid injection. This effect was mediated by PPARΥ (Esposito et al., 2011). In Alzheimer-prone AβPP/PS1 transgenic mice, application of THC in combination with CBD. In early symptomatic stages, THC/CBD could revert both β Amyloid plaque formation and memory impairment. In late stages, plaque formation could not be prevented but memory could still be preserved by administration of THC and CBD (Aso et al., 2016). GPR3 has been previously linked to Alzheimer's disease. This receptor share about 35% of amino acid sequence with CB1 and CB2. CBD acts as an inverse agonist for this receptor as it has been shown in a β-arrestin2 recruitment assay (Laun & Song, 2017).

A comparative study into the topical anti-inflammatory activity of cannabinoids (on croton oil-inflamed skin in mice) showed that Δ8THC, Δ9THC and THCV are about half as effective in reducing inflammation as Indometacin (a commonly used Non-steroid anti-inflammatory drug), but approximately 5 times more effective than CBCV and CBD. CBC and CBDV had no appreciable anti-inflammatory activity (Tubaro et al., 2010)

Several studies have pointed out a correlation between the occurrence of OCD and cannabis use (De Alwis et al., 2014; Bidwell et al., 2014; Loflin et al., 2014). However, whether cannabis use precipitates OCD or cannabis is used to self-medicate against the symptoms of OCD remains to be elucidated.

In the 6-OH-DOPA mouse model of Parkinson’s daily administration of either THC or CBD provided lasting neuroprotection (Lastres-Becker et al., 2005). In a rat model of Parkinson’s Disease, THCV and CBD were neuroprotective in a CB2-independent way (García et al., 2011). In cultured midbrain neurons, CBD, THCA and THC had anti-oxidative properties. Moreover, THCA and THC were shown to be neuroprotective (Moldzio et al., 2012). GPR6 has been previously linked to Parkinson's disease. This receptor share about 35% of amino acid sequence with CB1 and CB2. CBD acts as an inverse agonist for this receptor as it has been shown in a β-arrestin2 recruitment assay (Laun & Song, 2017).

Anti-psychotic drugs often antagonize dopamine D2 receptors. In apoMorphine- or amphetamine treated rats 15-60 mg/kg CBD reduced stereotyped behavior and hyperlocomotion similar to haloperidol in a dose-dependent manner. At 120-480 mg/kg (!!!) CBD increased prolactin levels (like haloperidol) but did not induce catalepsy (unlike haloperidol) suggesting CBD has anti-psychotic potential at high doses (reviewed in Zuardi et al., 2006). In patients with acute schizophrenia, AEA levels are elevated and inversely correlated with psychotic symptoms, suggesting involvement of the endocannabinoid system in the regulation of Psychosis (Giuffrida et al., 2004). At 27.5 μM CBD can AEA inactivation and indirectly increase AEA levels (Bisogno et al., 2001). In a small-scale clinical trial up to 4 doses of 200 mg CBD/day suppressed psychotic symptoms as effectively as amisulpride but with fewer side-effects (Leweke et al., 2012). Similarly, in several case reports CBD doses of up to 1500 mg/day for up to 4 weeks produced similar anti-psychotic effects as observed with classical anti-psychotics but with fewer side-effects (reviewed in Zuardi et al., 2006). It is known that THC can induce Psychosis-like effects in healthy volunteers. Using fMRI it was shown that 600 mg (oral capsule) could prevent Psychosis-like behavior induced by 10 mg THC (Bhattacharyya et al., 2010).

In both healthy volunteers and patients with Social Anxiety Disorder an oral dose of 600 mg CBD significantly reduced Anxiety, cognitive impairment and discomfort related to a public speaking assignment (Bergamaschi et al., 2011).

Two clinical trials in the 1980’s investigated the therapeutic properties of CBD in epilepsy. CBD was found to be effective in 50% of patients, meaning that seizure occurrence was reduced by >50%. The occurrence of seizures was reduced by less than 50% in a further 37.5% with no effect observed in the remaining 12.5% (Cunha et al., 1980; Pickering et al., 2011).

In one very public case, a girl with Dravet syndrome (loss of function mutation in the sodium channel SCN1A), went from having more than 50 convulsive seizures per day to less than 3 nocturnal seizures per month by using extract from a Cannabis variety Charlotte’s Web, which has a THC content of 0.5% and a CBD content of 17% (Maa and Figi, 2014). The authors stress that there is synergy between cannabinoids and that cannabis extracts are superior to individually purified cannabinoids.

In 8 patients 200-300 mg/day oral CBD was administered for up to 4.5 months. Fours patients became almost seizure-free, 3 patients showed partial improvement and one patient did not improve (Cunha et al., 1980).

In a small-scale clinical trial up to 4 doses of 200 mg CBD/day suppressed psychotic symptoms as effectively as amisulpride but with fewer side-effects (Leweke et al., 2012).

Similarly, in several case reports CBD doses of up to 1500 mg/day for up to 4 weeks produced similar anti-psychotic effects as observed with classical anti-psychotics but with fewer side-effects (reviewed in Zuardi et al., 2006).

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